Mai T. Pham; Pablo Cruz-Granados; Jose A. Lopez-Escamez

doi:10.21790/rvs.2025.010

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Review Article
Dissecting the genome in Ménière disease: a review: Mai T. Pham^1,2,*, Pablo Cruz-Granados^1,*, Jose A. Lopez-Escamez^1,3,4,5; Research in Vestibular Science 2025;24(3):139-152.
DOI: https://doi.org/10.21790/rvs.2025.010
Published online: September 15, 2025

¹Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, NSW, Australia

²Institute for Applied Research in Health Sciences and Aging (ARiHA) – Thong Nhat Hospital, Ho Chi Minh City, Vietnam

³Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Universidad de Granada, Granada, Spain

⁴Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, Madrid, Spain

⁵Hearing Therapeutics, Ear Science Institute Australia, Nedlands, WA, Australia

Corresponding author: Jose A. Lopez-Escamez Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, 10 Westbourne Street, St Leonards, NSW 2064, Australia. E-mail: jose.lopezescamez@sydney.edu.au

*These authors contributed equally to this study as co-first authors.

• Received: May 5, 2025 • Revised: May 23, 2025 • Accepted: June 9, 2025

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
INTRODUCTION
SPORADIC MÉNIÈRE DISEASE
FAMILIAL MÉNIÈRE DISEASE
INHERITANCE PATTERS IN FAMILIAL AND SPORADIC MÉNIÈRE DISEASE
CONCLUSIONS
ARTICLE INFORMATION
REFERENCES

Abstract

Ménière disease (MD) is a complex inner ear disorder characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. Despite its prevalence across European and Asian populations, along with five clinical subtypes with variable phenotypes and comorbidities, the molecular underpinnings of MD pathogenesis remain under investigation. This review aims to comprehensively summarize the genomic, epigenomic, and transcriptomic insights into MD, highlighting how these molecular layers contribute to disease susceptibility, progression, and phenotypic variability. Sporadic MD accounts for most diagnoses, where multifactorial mechanisms involving pathogenic rare variants, epigenetic modifications, and immune-related pathways contribute to disease risk. We also elucidate the genetic contribution of familial MD, in which inherited variants, primarily in genes involved in the extracellular structures of sensory epithelia and the stereocilia links of sensory cells, contribute to autosomal dominant, recessive, or digenic inheritance models. Furthermore, we explore the current use of animal models in validating gene pathogenicity. By integrating findings across multi-omics studies, this review emphasizes that MD is a polygenic and heterogeneous inherited disorder, with a spectrum of related conditions with common and distinct molecular origins. Understanding molecular mechanisms involving genetic and epigenetic factors is promising for biomarker discovery and future therapeutic interventions.
Keywords: Meniere disease; Genetics; Hearing loss; Autoimmune; RNA sequence analysis; Inner ear

INTRODUCTION

Ménière disease (MD) is a rare syndrome of the inner ear characterized by episodes of vertigo, sensorineural hearing loss (SNHL), tinnitus, and aural fullness [1,2]. The condition has a strong heritability according to familial aggregation studies [3] and more than 20 genes have been reported [4]. Diagnostic criteria for MD were first published in 1972 by the American Academy of Otolaryngology-Head and Neck Surgery and was last updated in the Bárány Society International Classification Committee for Vestibular Disorders in 2015, based on clinical symptoms reported by patients [2].

MD presents with a variable audiological phenotype and is associated with several comorbidities, some of which may not originate in the inner ear, such as migraine and autoimmune conditions like Hashimoto disease and rheumatoid arthritis [5]. Epidemiological studies have shown that MD is prevalent across Eurasia, with higher prevalence in Europe, with 530 and 135 MD patients per 100,000 individuals in Finland and Cantabria (northern Spain) [6]. In contrast, Japan and Taiwan have a prevalence of 3.5 and 75 MD cases per 100,000 inhabitants [6,7].

Histological studies have revealed anomalies in the temporal bone due to the accumulation of endolymphatic fluid, a condition known as endolymphatic hydrops [8]. It leads to an enlargement of the endolymphatic space, increasing pressure within the scala media. This pressure can damage the Reissner membrane, the basilar membrane, and the organ of Corti. However, endolymphatic hydrops have also been found in individuals with SNHL without MD [9].

To improve the understanding of the disease, a hierarchical cluster analysis identified five clinical subtypes in both unilateral and bilateral MD based on the onset of symptoms and associated comorbidities [10,11]. Clinical subtypes of MD include sporadic MD, delayed sporadic MD, familial MD, MD with migraine, and MD with an autoimmune disease.

The purpose of this review is to summarize the molecular basis of MD, outlining the epigenomic, genomic, and transcriptomic contributions to MD, which lead to the development of several phenotypes.

SPORADIC MÉNIÈRE DISEASE

About 70% to 90% of MD cases are considered of a sporadic nature. Genetic studies in sporadic MD are limited [12-15], as most sequencing studies have been done for familial cases [16].

Sporadic Ménière Disease-associated Genes

Over the past 5 years, the discovery of genes associated with sporadic MD has accelerated. In 2019, several genes associated with SNHL were reported to have an excess of rare missense variants [12]. Among these, six genes—GJB2, ESRRB, USH1G, and SLC26A4 were validated in two or more individuals and had high pathogenicity scores (Phred-scaled combined annotation dependent depletion score, >31). Furthermore, a novel synonymous variant was identified in the MARVELD2 genes in three unrelated MD patients.

Subsequently, a 2020 study focused on genetic variants associated with sporadic MD in the East Asian population [17]. This study identified 15 rare variants across 11 genes, including three genes previously associated with familial MD (DTNA, FAM136A, and DPT). Of the remaining nine genes, four genes—PTPN22, NFKB1, TLR2, and CXCL10—were associated with the immune response, while MTHFR, SLC44A2, NOS3, and NOTCH2 were associated with prothrombotic risk factors, possibly causing increased permeability of vascular endothelial cells.

A study focused on sporadic MD genetic landscape was published in 2024 [14]. Whole genome sequencing of 511 sporadic cases revealed rare variants in two genes MPHOSPH8 and MYO18A. The study presented a network analysis for molecular interactions and found 481 high-priority genes including TRIOBP, OTOGL, TNC, and MYO6. Furthermore, histology and in silico analysis unveiled that the genes involved in sporadic MD were highly expressed in auditory hair cells and vestibular dark cells.

However, the most frequent gene associated with sporadic MD is GJD3, which encodes the gap junction protein delta 3, also known as human connexin 31.9 (Cx31.9). Immunolabelling showed that Cx31.9 is found in the tectorial membrane (TM) [15]. A total of 18 MD patients including 10 familial cases (three unrelated families) and eight sporadic cases shared a rare haplotype (TGAGT) in the GJD3 coding sequence, composed of two missense, two synonymous, and one downstream variant. Although the electrophysiological characterization of the wild type and the mutated NP_689343.3:p.(His175Tyr) Cx31.9 hemichannels in Xenopus laevis oocytes demonstrated no differences in the current amplitudes, further studies including other haplotype variants are needed. Moreover, the variant g.40363293G > A, p.(His175Tyr) at the protein level, produces an amino acid change from a charged histidine to a hydrophobic tyrosine in the extracellular extreme of the connexon. Therefore, the loss of electrostatic interactions between His175 and Asp178 in each of the six connexins conforming the homomeric connexon alters the correct arrangement between two connexons to form the channel [15].

Immune Response in Sporadic Ménière Disease

The epigenome and transcriptome of sporadic MD have also been studied, as most sporadic MD patients suffer from immune dysregulation. Recent studies have classified patients with sporadic MD into three distinct immunophenotypes based on persistent inflammation and cytokine expression profiles: (1) a phenotype characterized by elevated levels of interleukin (IL)-1β and autoinflammation; (2) associated with high immunoglobulin E levels and Th2 cytokines with an allergy-like immune response; and (3) in conjunction with a comorbid autoimmune condition [18].

An epigenomic study [19] on peripheral blood mononuclear cells also classified sporadic cases into active and inactive groups. The active cluster was found to have differentially methylated CpGs (DMC) or differentially methylation regions (DMR) on several hearing loss (HL) genes, including PCDH15, ADGRV1, MYO15A, and CDH23. Furthermore, cytokine IL-32 was found to have both a DMC and a DMR in a promoter region. IL-32 is known to induce an inflammatory response led by IL-1β as reported in autoimmune and allergic conditions (systemic lupus, asthma, type 2 diabetes mellitus, allergic rhinitis) [20].

Bulk and single-cell RNA-sequencing [21,22] have demonstrated abnormal cell populations in two MD immune phenotypes. The allergic-like phenotype was described to have high levels of granulocytes and low levels of lymphocytes. On the other hand, the autoinflammatory phenotype had an active monocyte population compared to an MD cluster without immune imbalance.

Common variants with regulatory effects have been shown to influence the progression of HL in MD, including variants in nitric oxide synthases 1 and nitric oxide synthase, inducible (NOS1 and NOS2A genes) [23], major histocompatibility complex class I chain-related A (MICA) [24], toll-like receptors 10 (TLR10 gene) [25], and nuclear factor-kappa B (NF-κB) [26]. The studies found: (1) variants of no significance to MD (NOS1 and NOS2A genes); (2) several variants in exon 5 of MICA short tandem repeat possible association to HL in MD; (3) and variants of positive association to bilateral SNHL in MD (TLR10 gene), and unilateral SNHL (NF-κB).

Despite these findings on the immune response in sporadic MD patients, the link between immune dysregulation and rare genetic variants is yet to be elucidated.

FAMILIAL MÉNIÈRE DISEASE

Historical Perspective

Familial MD was first reported in 1949, when several unrelated families reported their family members in consecutive generations with partial MD symptoms, starting with spontaneous episodic vertigo, tinnitus, or HL as early-onset symptoms of MD [27,28]. Although several British families with MD were identified in the United Kingdom in the 20th century, genetic studies were limited by the existing technology [29]. However, over the past two decades, evidence from clinical reports and familial clustering with definite and probable MD [2] have supported the existence of a familial subtype of MD, highlighting a genetic contribution of this subtype. The first formal documentation of familial MD emerged in Spanish and Korean MD cohorts suggesting the prevalences of familial cases in these populations are approximately 8.4% and 6.3% of sporadic cases, respectively [3,30].

Familial MD is one of the five clinical subgroups, with approximately 13% of patients exhibiting a strong familial history [10,11]. Despite no significant differences in clinical characteristics between familial and sporadic cases, most familial cases exhibit early-onset MD phenotypes, accompanied by migraine [3,30].

There are three main inheritance patterns associated with familial MD, including autosomal dominant (AD) with incomplete/complete penetrance, autosomal recessive (AR), and digenic with multiallelic inheritance [16].

Gene Discovery in Familial Ménière Disease

Familial MD is an inherited heterogeneous disorder, characterized by a polygenic and multiallelic inheritance pattern with a large effect size. Over the past decade, there are many known and novel MD genes found in several unrelated families with high confidence, along with candidate genes with missense/nonsense rare variants identified in only one family (Fig. 1). Previous studies have reported approximately 20 familial MD genes [16,31], notably OTOG [32], MYO7A [33], and TECTA [34], which are three central SNHL genes in familial MD showing gene burden with an overload of rare variants in multiplex families. Recently, GJD3 has been discovered as a novel familial MD gene with a rare haplotype segregating the MD phenotypes in several unrelated families [15]. By contrast, most MD genes with rare variants were identified in one multiplex family and sporadic cases. The pathogenic role of these variants remains uncertain without replication in additional families, which requires further exome or genome sequencing data or variant-specific cellular or animal models to validate the clinical significance of these gene mutations.

The earliest genetic evidence for familial MD came from an exome sequencing study of a Spanish family with three affected members, leading to the identification of FAM136A and DTNA in 2015 as candidate genes following an AD inheritance pattern with incomplete penetrance [35]. The finding marked the first discovery of a familial inheritance model in MD.

Subsequent exome studies expanded the list of MD genes. In the next 2 years, rare variants in PRKCB [36], COCH [37], DPT [38], and SEMA3D [38] were sequentially reported in multiplex families mostly from Spain, with definite or probable MD, supporting the AD inheritance with incomplete penetrance. Later, the AR inheritance model was proposed for unrelated families from different populations, although most variants were found in only one family.

The identification of genes associated with familial MD has advanced significantly since 2020, when OTOG, the gene encoding otogelin, has emerged as one of the most frequently mutated genes in several familial and sporadic cases, supporting the compound heterozygous AR inheritance. In 2021, Roman-Naranjo et al. also reported potential digenic inheritance involving MYO7A, CDH23, PCDH15, and ADGRV1 genes. They are also causative genes following monogenic AR inheritance in Usher syndrome. TECTA is another notable MD gene for the AD pattern with rare variants found in two unrelated families [34]. The most recent finding, GJD3, was discovered in 2025 in families with AR inheritance [15].

Other emerging MD candidate genes, including DPT [17], OTOP1 [39], and OTOP2 [39], have recently been reported in a single proband with early or adult onset, thus requiring further investigation. Collectively, these findings highlight the genetic complexity and heterogeneity of familial MD, encompassing different inheritance patterns with multiple variants reported, thereby reinforcing the need for continued genetic research in animal models of MD.

Localization and Functional Role of Ménière Disease Genes in the Inner Ear

A schematic representation of gene expression and protein localization in the inner ear provides critical insights into the molecular interactions, functional roles, and underlying mechanisms associated with the pathophysiology of MD symptoms (Fig. 2, [15,16,35,36,40-45], Table 1 [33,36,39,45-85]). Several notable MD genes and their protein products have been validated through high-throughput sequencing and qPCR for gene expression, as well as immunofluorescence for protein localization in the cochlear and vestibular systems. Mutant forms of these genes have been developed in animal systems to study gene functions associated with HL and vestibular deficits, providing strong evidence for their critical roles in MD pathophysiology.

The vertebrate inner ear is composed of two primary sensory systems: the auditory organ, termed the organ of Corti in mammals, located in the cochlea, responsible for sound sensing and the vestibular system, which includes the utricle, saccule, and semicircular canals, responsible for acceleration detection [86]. Hair cells, the mechanosensory cells of the inner ear, convert mechanical energy from sound or head movements into electrical impulses that are transmitted to afferent neurons. These cells are surrounded by several types of supporting cells in the organ of Corti, for structural support, ion homeostasis, signaling crosstalk via junction proteins, and regeneration of hair cells [87]. The mechanosensitive organelles of hair cells are the stereocilia (or hair bundle) responsible for the mechanoelectrical transduction (MET) process, a fundamental function of hair cells [87,88]. When sound or motion causes the stereocilia to deflect, MET channels located at the tip links open, allowing ions, especially potassium (K^⁺) and calcium (Ca^2⁺), to flow into the cell. This depolarises hair cells and initiates neurotransmitter release. The clinical significance of proteins directly involved in the stereocilia bundle and MET channel is explained by many single-gene mutations linked to SNHL of Usher syndrome. These genes have also been reported in bi-allelic inheritance in MD [16], where co-occurring mutations result in disorganized stereocilia and a reduction in MET current amplitude, thereby resulting in reduced auditory function, increased susceptibility to sound-induced damage, and progressive HL. Otogelin (OTOG), α-tectorin (TECTA), connexin-31 (GJD3), and stereocilin (STRC) are structural proteins localized in stereocilia and/or TM, as well as at the stereocilia-TM attachment site, also involved in MET process and TM structural integrity.

In the vestibular system, otogelin is also expressed, along with otolith-related proteins such as the otopetrin family, which are essential for otoconia formation and maintenance, contributing to gravity sensing for the proper vestibular function [40,41,46]. Otopetrins act as a sensor of the extracellular Ca²⁺ near supporting cells and respond to ATP in the endolymph to increase intracellular Ca²⁺ during otoconia mineralization [40]. Mutations in OTOP genes have been found in patients with non-syndromic vestibular dysfunction and MD [39].

Other MD genes encode proteins primarily enriched in cochlear and/or vestibular supporting cells, where their mutant forms contribute to HL. PRKCB (protein kinase β) and LSC6A7 (solute carrier family 6 member 7) have been implicated in the development of endolymphatic hydrops, a histologic marker of MD [36,47]. Notably, COCH (cochlin) is uniquely expressed in the lateral wall of cochlear and plays a role in innate immunity from pathogenic infection and inflammation, potentially linking immune responses to MD pathogenesis [42,48,49].

While the localization of some MD genes or proteins is nonspecific to particular cell types in the inner ear, their mutant forms are implicated in autoimmune diseases, oxidative stress, inflammation, HL, and vestibular defects. Together, deciphering the spatial localization of MD genes and their protein products provides us valuable insights into the structural architecture, biomechanical functions, and cellular interactions of the cochlear and vestibular systems in the inner ear. Disruptions to these elements attributed to gene mutations result in dysfunctional hearing and balance systems that underline the clinical manifestations of MD.

Animal Models

Animal models, particularly mouse models, have been commonly used in studying gene functions and phenotypic consequences of pathogenic variants in key deafness-related genes, such as MYO7A, CDH23, OTOG, and TECTA, due to their moderate-to-high genomic homology with human in SNHL and Usher syndrome [4]. Comparable inner ear architecture between mice and humans also supports the use of mouse models in elucidating the pathophysiology of auditory and vestibular disorders [89]. Several cochlear defects, such as disorganized stereocilia bundle, degeneration of hair cells, or TM defects, have been discovered through mouse models carrying the relevant mutations in key deafness genes associated with MD-like syndromes [89]. In addition, mouse mutants have been developed to study MD genes associated with non-syndromic vestibular dysfunction or balance deficits, such as DTNA, COCH, OTOP1, and HMX2, supporting their crucial roles in maintaining proper vestibular functions.

Notably, knockout (KO) and heterozygous mutant (HET-mut) models for FAM136A and DTNA, which are known as MD genes linked to the AD inheritance model of familial MD, have been generated for functional analysis [50]. While KO and HET-mut mice for FAM136A show progressive HL, DTNA mutants exhibit balance deficits. It supports the AD inheritance model of both genes [35], since heterozygous or homozygous mutations in these genes lead to HL and balance-related symptoms, with homozygous forms showing more severe phenotypes [50].

Besides mouse models, alternative systems such as the fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio) offer cost-effective models for studying hereditary HL in humans [4]. The Johnston’s organ in Drosophila, functionally analogous to the human organ of Corti, contains scolopidia, a mechanosensitive unit like mammalian hair cells. These structural and functional similarities make Drosophila a valuable model for auditory research. Zebrafish is also a potential candidate system for inner ear research, since it has several resemblances to the mammalian hearing organ, such as neuromasts containing hair cells. These two non-murine models have been employed in MD gene studies. For example, OTOP1-KO in zebrafish causes the impairment of otoconia formation and maintenance, leading to non-syndromic vestibular dysfunction [51]. In Drosophila, Dyb mutants, orthologs of DTNA, result in HL and impaired auditory homeostasis [52].

The role of other MD candidate genes, such as TMEM55, LSC6A7, DPT, OTOP2, PRKCB, and SEMA3D, in the inner ear remains unclear. Further, in vivo studies are needed to investigate the pathogenic effects of these genes in the inner ear, and to elucidate their contribution to specific MD phenotypes.

INHERITANCE PATTERS IN FAMILIAL AND SPORADIC MÉNIÈRE DISEASE

Sporadic Ménière Disease

Most MD cases are classified as sporadic, typically characterized by the absence of a familial history. Familial MD, on the other hand, is defined when more than one individual within a multi-generational family fulfills all clinical criteria for definite MD [2] (Fig. 3). While familial cases are mostly found with rare monogenic or digenic inheritance models with moderate-to-high impact single nucleotide variants (missense/nonsense) or a haplotype, sporadic MD is likely shaped by a polygenic model, in which multiple low-effect size variants contribute to disease risk.

Autosomal Dominant Inheritance

AD is the most common inheritance pattern observed in clinical practice and the starting point for discovering familial MD. In this mode, a single mutated allele from one affected parent is sufficient to confer disease susceptibility, with a 50% chance of transmission to offspring [90]. In MD, AD with incomplete penetrance is more frequently reported [3,30], when individuals carrying pathogenic variants remain asymptomatic or present partial symptoms, likely due to the functional compensation of other genes or the lack of the triggering environmental factor.

The most common AD genes in MD are GJD3, TECTA, and MYO7A, all reported in Spanish families with MD [15,33,34]. Genes such as FAM136A, DTNA, PRKCB, COCH, DPT, and SEMA3D have been associated with AD inheritance in Spanish and Korean multiplex families. Particularly, variants of these genes segregate with incomplete/complete penetrance in multiple reported families. The presence of these rare genetic variants increases MD susceptibility, but molecular mechanisms leading to MD require further investigations.

Autosomal Recessive Inheritance

AR inheritance in familial MD is not easy to identify since familial cases may be second-degree relatives. They typically require biallelic pathogenic variants, for example, one faulty allele inherited from each parent [90]. This mode often results in earlier disease onset, sometimes evident in childhood, and may manifest with more severe phenotypes in many genetic disorders [91].

Genes with rare missense variants include STRC [92], LSAMP [93], TMEM55B [94], and HMX2 [94]. However, the most common gene found in AR MD is OTOG, commonly reported in Spanish unrelated families showing compound recessive inheritance [32].

Digenic Inheritance

Digenic/polygenic inheritance refers to conditions that require rare variants at two distinct loci of different genes for disease phenotypes to be manifested [90]. Emerging evidence suggests that variants in MYO7A and secondary genes, such as CDH23 and ADGRV1, which are involved in hair cell stereocilia links, play a joint role in a digenic inheritance model in familial MD [33]. This inheritance model reflects the complex genetic architecture and potential gene–gene interactions in MD.

CONCLUSIONS

MD is a multifactorial disorder with a significant heritability. Rare genetic variations linked to familial MD pathogenesis are primarily found in genes related to the stereocilia links of hair cells and TM in the organ of Corti, including OTOG, TECTA, and MYO7A. Conversely, sporadic MD accounts for most cases and is associated with altered immune response and systemic inflammation. Interestingly, GJD3 has emerged as a novel gene found in both sporadic and familial MDs, supporting a common link in the pathogenesis of the disease.

ARTICLE INFORMATION

Funding/Support

This research was funded by a grant from The University of Sydney (K7013-B3414G).

Conflicts of Interest

Jose A. Lopez-Escamez is an Editorial Board member of Research in Vestibular Science and was not involved in the review process of this article. The authors declare no other conflicts of interest.

Availability of Data and Materials

The datasets are not publicly available but are available from the corresponding author upon reasonable request.

Authors’ Contributions

Conceptualization, Funding acquisition: Lopez-Escamez JA; Formal analysis, Visualization: Pham MT, Cruz-Granados P; Writing–original draft: All authors; Writing–review and editing: All authors

All authors read and approved the final manuscript.

Fig. 1.

Chronological discovery of familial Ménière disease (MD) genes. The upper half of the graph shows familial MD genes found in more than one family and/or sporadic cases, and the bottom half familial MD genes found in one family or sporadic cases. Most familial studies have been performed in the non-finished European population, the most common gene being OTOG. AD, autosomal dominant; AR, autosomal recessive.

Fig. 2.

Illustrative presentation of Ménière disease (MD) genes and their protein expression in the cochlear and vestibular system. Known, validated by high-throughput sequencing, quantitative polymerase chain reaction (gene expression), or immunofluorescence (protein localization) (red) – OTOG, MYO7A, CDH23, PCDH15, ADGRV1, USH1C, STRC [16,43]; TECTA [44]; COCH [42,43]; GJD3 [15]; OTOP1 [40,41]; OTOP2 [45]; PRKCB [36]; DTNA, FAM136A [35]; Implicated by inner ear gene expression databases (gEAR: https://umgear.org–green). Created in BioRender (Lopez-Escamez J [2025]. https://BioRender.com/aka21ad).

Fig. 3.

Pedigrees of sporadic Ménière disease (MD) and familial MD with its inheritance models. Created in BioRender (Lopez-Escamez J [2025]. https://BioRender.com/aka21ad).

Table 1.

Summary of Ménière disease genes

Type	Gene	Protein	Function in inner ear	Clinical significance
Cochlear HC (stereocilia links + MET complex)	MYO7A	Myosin VIIa	Involved in structural and functional integrity of stereocilia, Ca²⁺ homeostasis, and MET process [33]	USH1B [53]; KO in mice causes disorganized stereocilia and progressive HL [54,55]
	CDH23	Cadherin-23		USH1D [56]; KO and HET-mut in mice lead to disorganized stereocilia, noise-induced and progressive HL [54]
	PCHDH15	Protocadherin-15		USH1F [57]; gene therapy in mouse USH1F model effectively restores hearing and balance [58]
	ADGRV1	ADGRV1		USH2C [59]; KO in mice causes HL [60]
	USH1C	Harmonin		USH1C, DFNB18A [61]
Stereocilia-TM attachment	STRC	Stereocilin	Linking adjacent stereocilia [62]	KO mice lack horizontal top connectors, leading to progressive HL [71]
	GJD3	Human connexin 31.9 (Cx31.9)	A gap junction involved in Ca²⁺ signaling [63]	DFNB2B [64]; KO of Connexin genes (GJD2/GJD6) in mice leads to degeneration of sensory epithelium, profound hearing impairment, even lethality [65]
	OTOG	Otogelin	Organizing and stabilizing fibrillar network (TM) [65]	KO in mice causes deafness - a candidate gene for human NSHL [66]
	TECTA	a-tectorin	TM formation + MET process [67]	AD-NSHL [67]
Vestibular and/or cochlear SC enriched	PRKCB	Protein Kinase b	K⁺ recycling within endolymph [36]	Associated with onset of low-frequency SNHL [36]
	SEMA3D	Semaphorin 3D	Involved in axonal guidance signaling [68]	-
	LSAMP	Limbic system-associated membrane	A neuronal surface adhesion glycoprotein	KO mice exhibit lower anxiety and decreased agonistic behavior [70]
	LSAMP	Limbic system-associated membrane	in cortical and subcortical regions of the limbic system, associated with auditory processing and tinnitus [69]
	COCH	Cochlin	The most abundant proteins in the inner ear [48]	KO in mice causes late-onset HL with variable vestibular dysfunction [71]; DFNA9 and DFNB110 [48]
	DTNA	a-dystrobrevin	A cytoskeletal protein required for signaling between the neurons and SCs [52]; associated with aquaporin-4, enabling osmotic water flow in vestibular sensory epithelia to regulate endolymph volume and Ca²⁺ homeostasis [72]	Dyb mutant fly leads to HL and auditory homeostasis deficit [52]; KO and HET-mut mice primarily show balance deficits [51]; possibly involved in endolymphatic hydrops [72]
Otolith-related proteins	OTOG	Otogelin	Required for an attachment of the otoconial membranes to the neuroepithelia [65]	KO in mice causes severe imbalance [65]
Otolith-related proteins	OTOP1/2	Otopetrin-1/2	Otoconia formation and maintenance [45,46]	OTOP1-KO in zebrafish and mice causes non-syndromic vestibular dysfunction due to impaired otoconia formation [51]
Immunity	COCH	Cochlin	Possibly protecting the inner ear from infection [48]	KO mice show reduced immune responses to bacterial infection [49]
Others	TMEM55B	Transmembrane 55	Contributing to lysosomal homeostasis and mTOR signaling [73]. mTOR signaling involved in trans-differentiation of SC into HC and in HC death [74]	Variants/KO mice in TMEM family associated with HL [75,76]
	SLC6A7	Solute carrier family 6 member 7	A soluble carrier protein that transports sugars, amino acids, nucleotides, and drugs	Disruption of SLC transporters in guinea pig associated with oxidation stress and inflammation [77]; Other LSC family members involved in MD pathogenesis in a murine endolymphatic hydrops model [47]; NSHL and enlarged vestibular aqueduct [78]
	FAM136A	Family, with sequence similarity 136, member A	A mitochondrial protein involved in electron/oxygen transport chain of respiration	KO and HET-mut mice primarily show progressive HL [50]
	ECM1	Extracellular matrix 1	-	HET-mut mice showing decreased neutrophil cells, likely associated with autoimmune diseases; associated with non-syndromic vestibular dysfunction [39]
	GUSB	glucuronidase beta	A lysosomal enzyme essential for degradation of GAGs [79,80]	Associated with AR lysosomal storage disease in the brain (MPS VII) [90]; In a mouse model for MPS VII, SNHL associated with altered cochlear structure and vestibular dysfunction [82,83]
	HMX2	Homeobox-2	Required for vestibular structure and development; specification of vestibular HC and SC types [84]	KO in mice leads to defects in vestibular structure and function [84]. Compound (HMX2/HMX3) mutant mice cause severe defects
	DPT	Dermatopontin	An extracellular matrix protein inhibits the formation of decorin-TGFb1 complex on endothelial cell surface to maintain vascular homeostasis [85]	-

AD-NSHL, autosomal dominant non-syndromic hearing loss; SNHL, sensorineural hearing loss; HL, hearing loss; USH, Usher syndrome; TM, tectorial membrane; MET, mechanoelectrical transduction; HC, hair cell; SC, supporting cell; KO, knockout (homozygous mutant –/–); mTOR, mechanistic target of rapamycin; HET-mut, heterozygous mutant +/–; AR, autosomal recessive; MPS VII, mucopolysaccharidosis VII; GAG, glycosaminoglycan; TGFβ1, transforming growth factor beta 1.

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Dissecting the genome in Ménière disease: a review

Res Vestib Sci. 2025;24(3):139-152. Published online September 15, 2025

DOI: https://doi.org/10.21790/rvs.2025.010

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Dissecting the genome in Ménière disease: a review

Fig. 1. Chronological discovery of familial Ménière disease (MD) genes. The upper half of the graph shows familial MD genes found in more than one family and/or sporadic cases, and the bottom half familial MD genes found in one family or sporadic cases. Most familial studies have been performed in the non-finished European population, the most common gene being OTOG. AD, autosomal dominant; AR, autosomal recessive.

Fig. 2. Illustrative presentation of Ménière disease (MD) genes and their protein expression in the cochlear and vestibular system. Known, validated by high-throughput sequencing, quantitative polymerase chain reaction (gene expression), or immunofluorescence (protein localization) (red) – OTOG, MYO7A, CDH23, PCDH15, ADGRV1, USH1C, STRC [16,43]; TECTA [44]; COCH [42,43]; GJD3 [15]; OTOP1 [40,41]; OTOP2 [45]; PRKCB [36]; DTNA, FAM136A [35]; Implicated by inner ear gene expression databases (gEAR: https://umgear.org–green). Created in BioRender (Lopez-Escamez J [2025]. https://BioRender.com/aka21ad).

Fig. 3. Pedigrees of sporadic Ménière disease (MD) and familial MD with its inheritance models. Created in BioRender (Lopez-Escamez J [2025]. https://BioRender.com/aka21ad).

Fig. 1.

Fig. 2.

Fig. 3.

Dissecting the genome in Ménière disease: a review

Type	Gene	Protein	Function in inner ear	Clinical significance
Cochlear HC (stereocilia links + MET complex)	MYO7A	Myosin VIIa	Involved in structural and functional integrity of stereocilia, Ca²⁺ homeostasis, and MET process [33]	USH1B [53]; KO in mice causes disorganized stereocilia and progressive HL [54,55]
	CDH23	Cadherin-23		USH1D [56]; KO and HET-mut in mice lead to disorganized stereocilia, noise-induced and progressive HL [54]
	PCHDH15	Protocadherin-15		USH1F [57]; gene therapy in mouse USH1F model effectively restores hearing and balance [58]
	ADGRV1	ADGRV1		USH2C [59]; KO in mice causes HL [60]
	USH1C	Harmonin		USH1C, DFNB18A [61]
Stereocilia-TM attachment	STRC	Stereocilin	Linking adjacent stereocilia [62]	KO mice lack horizontal top connectors, leading to progressive HL [71]
	GJD3	Human connexin 31.9 (Cx31.9)	A gap junction involved in Ca²⁺ signaling [63]	DFNB2B [64]; KO of Connexin genes (GJD2/GJD6) in mice leads to degeneration of sensory epithelium, profound hearing impairment, even lethality [65]
	OTOG	Otogelin	Organizing and stabilizing fibrillar network (TM) [65]	KO in mice causes deafness - a candidate gene for human NSHL [66]
	TECTA	a-tectorin	TM formation + MET process [67]	AD-NSHL [67]
Vestibular and/or cochlear SC enriched	PRKCB	Protein Kinase b	K⁺ recycling within endolymph [36]	Associated with onset of low-frequency SNHL [36]
	SEMA3D	Semaphorin 3D	Involved in axonal guidance signaling [68]	-
	LSAMP	Limbic system-associated membrane	A neuronal surface adhesion glycoprotein	KO mice exhibit lower anxiety and decreased agonistic behavior [70]
	LSAMP	Limbic system-associated membrane	in cortical and subcortical regions of the limbic system, associated with auditory processing and tinnitus [69]
	COCH	Cochlin	The most abundant proteins in the inner ear [48]	KO in mice causes late-onset HL with variable vestibular dysfunction [71]; DFNA9 and DFNB110 [48]
	DTNA	a-dystrobrevin	A cytoskeletal protein required for signaling between the neurons and SCs [52]; associated with aquaporin-4, enabling osmotic water flow in vestibular sensory epithelia to regulate endolymph volume and Ca²⁺ homeostasis [72]	Dyb mutant fly leads to HL and auditory homeostasis deficit [52]; KO and HET-mut mice primarily show balance deficits [51]; possibly involved in endolymphatic hydrops [72]
Otolith-related proteins	OTOG	Otogelin	Required for an attachment of the otoconial membranes to the neuroepithelia [65]	KO in mice causes severe imbalance [65]
Otolith-related proteins	OTOP1/2	Otopetrin-1/2	Otoconia formation and maintenance [45,46]	OTOP1-KO in zebrafish and mice causes non-syndromic vestibular dysfunction due to impaired otoconia formation [51]
Immunity	COCH	Cochlin	Possibly protecting the inner ear from infection [48]	KO mice show reduced immune responses to bacterial infection [49]
Others	TMEM55B	Transmembrane 55	Contributing to lysosomal homeostasis and mTOR signaling [73]. mTOR signaling involved in trans-differentiation of SC into HC and in HC death [74]	Variants/KO mice in TMEM family associated with HL [75,76]
	SLC6A7	Solute carrier family 6 member 7	A soluble carrier protein that transports sugars, amino acids, nucleotides, and drugs	Disruption of SLC transporters in guinea pig associated with oxidation stress and inflammation [77]; Other LSC family members involved in MD pathogenesis in a murine endolymphatic hydrops model [47]; NSHL and enlarged vestibular aqueduct [78]
	FAM136A	Family, with sequence similarity 136, member A	A mitochondrial protein involved in electron/oxygen transport chain of respiration	KO and HET-mut mice primarily show progressive HL [50]
	ECM1	Extracellular matrix 1	-	HET-mut mice showing decreased neutrophil cells, likely associated with autoimmune diseases; associated with non-syndromic vestibular dysfunction [39]
	GUSB	glucuronidase beta	A lysosomal enzyme essential for degradation of GAGs [79,80]	Associated with AR lysosomal storage disease in the brain (MPS VII) [90]; In a mouse model for MPS VII, SNHL associated with altered cochlear structure and vestibular dysfunction [82,83]
	HMX2	Homeobox-2	Required for vestibular structure and development; specification of vestibular HC and SC types [84]	KO in mice leads to defects in vestibular structure and function [84]. Compound (HMX2/HMX3) mutant mice cause severe defects
	DPT	Dermatopontin	An extracellular matrix protein inhibits the formation of decorin-TGFb1 complex on endothelial cell surface to maintain vascular homeostasis [85]	-

Table 1. Summary of Ménière disease genes